A primary human xenograft model of pancreatic cancer.

描述(申请人提供)：胰腺癌患者的五年生存率低于5%。几种新的治疗方法在小鼠胰腺癌模型中被证明是非常有效的；然而，在人类临床试验中，这些药物都失败了。迫切需要更准确地反映患者疾病进展过程的胰腺癌临床前模型。这项建议的目的是利用原发的人肿瘤移植到免疫缺陷小鼠的胰腺内，建立一种原位小鼠胰腺癌模型。该模型的一个关键组成部分将是肿瘤的遗传和分子特征及其与肿瘤生物学行为(例如分级、侵袭性)的相关性。正位模型是基于文献中描述的研究和PI以前的工作。建立一个强大的、具有良好特性的原位模型将有助于在个体化治疗药物的基础上进行临床前测试，这些药物针对的是对胰腺癌进展和转移至关重要的明确的信号通路。推动该模型发展的一个中心假设是，将原发人类异种移植物原位植入胰腺将更接近人类胰腺癌的生长环境。因此，对原位移植肿瘤的分子和细胞分析应该更准确地反映单个患者肿瘤的生物学行为，从而能够评估每个肿瘤中细胞表面受体的表达/激活和激活的细胞信号通路。实验计划详细说明了以下两个具体目标：1)收集人胰腺癌标本，然后在小鼠体内原位繁殖肿瘤，并评估生长动力学、肿瘤侵袭和转移。2)对人肿瘤和异种移植肿瘤进行分子表征，并将每个肿瘤的分子信号特征与其生长、侵袭和转移行为相关联。虽然以前的研究已经描述了胰腺肿瘤的皮下和原位移植，但本文描述的模型将是首次尝试将胰腺肿瘤的临床特征与胰腺内原位生长的肿瘤的分子和细胞属性相关联。除了提供有关原发胰腺癌分子和细胞特性的基本信息外，该模型的开发将是实现胰腺癌个性化治疗的下一步。公共卫生相关性：胰腺癌是美国癌症死亡的第四大原因，是所有癌症中存活时间最短的。我们的目标是开发一种治疗胰腺癌的新方法，根据每个患者特定肿瘤的最佳治疗目标，为他们提供个性化的治疗。我们计划通过开发一种小鼠胰腺癌模型来实现这一点，在该模型中，患者的部分肿瘤生长在小鼠胰腺中，然后评估它们的分子特征和对治疗的反应。

DESCRIPTION (provided by applicant): The five-year survival for patients with pancreatic cancer is less than 5%. Several novel therapies have been shown to be highly effective in mouse models of pancreatic cancer; however, in human clinical trials these agents have failed. There is a compelling need for preclinical models of pancreatic cancer that more accurately reflect the process of disease progression in patients. The objective of this proposal is to develop an orthotopic mouse model of pancreatic cancer using primary human tumors implanted into the pancreas of immune compromised mice. A key component of this model will be the genetic and molecular characterization of tumors and correlation of this with the biologic behavior of the tumors (e.g. grade, invasiveness). The orthotopic model is based on studies described in the literature and previous work of the PI. The establishment of a robust and well characterized orthotopic model will facilitate preclinical testing on an individualized basis of therapeutic agents that target defined signaling pathways important for pancreatic cancer progression and metastasis. A central hypothesis driving the development of the model is that orthotopic implantation of primary human xenografts into the pancreas will more closely recapitulate the growth environment of human pancreatic cancers. Thus, the molecular and cellular analysis of the orthotopically implanted tumors should more accurately reflect the biologic behavior of individual patient tumors, allowing the assessment of the repertoire of cell surface receptor expression/activation and cell signaling pathways activated in each tumor. The Experimental Plan details the following two specific aims: 1) To collect human pancreatic cancer specimens then propagate tumors orthotopically in mice and evaluate growth kinetics, tumor invasion, and metastasis. 2) To perform molecular characterization of human and xenografted tumors and correlate the molecular signaling profile of each tumor with its growth, invasive, and metastatic behavior. While previous studies have described the transplantation of pancreatic tumors subcutaneously and orthotopically, the model described herein will be the first attempt to correlate the clinical properties of pancreatic tumors with the molecular and cellular properties of the tumors propagated orthotopically in the pancreas. In addition to providing fundamental information about the molecular and cellular properties of primary pancreatic cancers, development of this model will be the next step toward arriving at a personalized approach to therapy for pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading cause of cancer deaths in the United States and has the shortest survival time of any cancer. Our goal is to develop a novel approach to therapy for pancreatic cancer, with treatment individualized for each patient depending on the best target for therapy of their specific tumor. We plan to achieve this by developing a mouse model of pancreatic cancer in which portions of patients' tumors are grown in the mouse pancreas, and then assessed for their molecular characteristics and response to treatment.